Abstract
Ouabain is a highly polar and unusually potent sodium pump inhibitor that possesses uncommon conformational flexibility in its steroid A-ring moiety. The biological significance of ring flection in the cardiotonic steroids has not been described. Accordingly, we prepared ouabain 1,5,19- and 1,11,19-phosphates. The former stabilizes the steroid A-ring chair conformation and the latter locks the A-ring in the half-boat conformation and decreases flection of the ABC-ring moiety. Using a dog kidney cell line (MDCK) in a pH microphysiometer (Cytosensor), ouabain and its 1,5,19-phosphate at 10(-5) M reduced the rate of extracellular acidification by 15-20%. During inhibitor washout, the rate of recovery from the 1,5,19-phosphate analogue was approximately 3 times faster than ouabain. The 1,11,19-phosphate at 10(-4) M elicited a weak ( approximately 7%) response, and the effects reversed approximately 44-fold faster than ouabain. Studies with purified Na(+),K(+)-ATPase showed that ouabain and its 1,5,19-phosphate analogue were of similar efficacy (EC(50) = 1.1 and 5.2 x 10(-7) M, respectively) and >100-fold more potent than the 1,11,19-phosphate analogue. Studies of the binding kinetics showed that the 1,5,19-phosphate analogue bound ...Continue Reading
References
Aug 1, 1987·The American Journal of Physiology·R M Lynch, R S Balaban
Oct 1, 1984·Journal of Cellular Physiology·B G Kennedy, J E Lever
Jan 1, 1994·Annual Review of Biophysics and Biomolecular Structure·J C OwickiJ W Parce
Feb 1, 1996·Journal of Hypertension·J M HamlynP Manunta
Citations
Dec 3, 2005·Breast Cancer Research and Treatment·Jin-Qiang ChenJose Russo
Mar 16, 2011·Clinical and Experimental Pharmacology & Physiology·Masamichi YoshikaHakuo Takahashi
Nov 1, 2001·Proceedings of the National Academy of Sciences of the United States of America·O AizmanA Aperia
Dec 1, 2015·Chemistry : a European Journal·Kengo MasudaMasayuki Inoue
Aug 1, 2009·ChemMedChem·Fatima Bousejra-El GarahAnne Robert
May 24, 2003·Annals of the New York Academy of Sciences·John M HamlynBruce P Hamilton
May 24, 2003·Annals of the New York Academy of Sciences·Oleg Aizman, Anita Aperia
Mar 19, 2009·Chemistry, an Asian Journal·Maddi Sridhar ReddyPierre Deslongchamps
Feb 23, 2012·Chemistry : a European Journal·Brian Heasley
Dec 19, 2002·Biochimica Et Biophysica Acta·Franz KerekLuis Moroder
May 23, 2006·Cellular Signalling·Jaehoon JungKyunglim Lee
May 26, 2006·The Journal of Biological Chemistry·Songbai ZhangAnita Aperia
Sep 1, 2017·Journal of Cellular Biochemistry·Israel José Pereira GarciaHérica de Lima Santos
Jan 27, 2004·Molecular Pharmacology·Gilles CrambertKäthi Geering
Nov 2, 2014·Chemical Research in Toxicology·Karl M WeigandJan B Koenderink
Jan 17, 2015·Journal of the American Chemical Society·Hans RenataPhil S Baran
Dec 20, 2002·Organic Letters·Zhixiang YangPierre Deslongchamps